Nearly 20% of all human tumors have been linked to mutations in the RAS family of proteins making RAS one of the most sought after targets for chemotherapeutic intervention. Within the RAS family, oncogenic mutations in the isoform, KRAS, account for nearly 85% of all of those mutations. Despite significant research efforts, the development of small-molecule pharmacologic agents targeted at RAS has been largely unsuccessfully. As an alternative, we are seeking to identify D-peptide ligands of KRAS mutants targeted at KRAS protein-protein interactions as potential cancer therapeutics. Using the tools of chemical synthesis, we will generate homogeneous KRAS mutants using D-amino acids. These D-enantiomers of our target oncogenic mutants will be screened against large peptide libraries utilizing mirror-image phage display technology. Taking advantage of the principles of this technology, L-peptide ligands of D-KRAS mutants will be prioritized according to binding affinity. This accomplished, the corresponding peptides in the D-series will be synthesized. Of course these will have equal affinities with the endogenous L-KRAS mutants. Their biological activity will then be examined. This proposal describes an early-stage cancer drug development program that appears to have great promise for identifying lead compounds to be advanced into pre-clinical drug development in the future.